ProjectSummary?Project1 Our previous data have shown that the aged microenvironment drives resistance to targeted therapy, and may impact response to immunotherapyas well. Tumor cells undergo metabolic reprogramming in order to acquire resistance to BRAF/MEK inhibitors. We have found that one of the contributing factors to this resistance may be lipids. Aged or stressed fibroblasts secrete lipids, whichare takenup by melanoma cells, promoting their ability to invade, and resist targeted therapy. These stromally-induced changes can also affect immune cells. Dendritic cells (DC) are required for the initiation and maintenance of immune responses and lipid accumulation in DC decreases their ability to act as antigen presenting cells. Myeloid derivedsuppressorcells(MDSCs)playamajorroleinregulationofantitumorimmunity.Thesecellsthriveon lipidmetabolismandtheyaccumulateanduseoxidizedlipidstoaugmenttheirabilitytosuppresstheimmune microenvironment.Wehaveimplicatedfattyacid(FA)transporterprotein2(FATP2)inlipidaccumulationby bothtumorcellsandPMN-MDSC,suggestingacomplexcrosstalkbetweenmultiplecomponentsoftheTME. We propose to identify the mechanism and subsequent functional consequences of lipid accumulation in tumorcellsandMDSCs. WewillevaluatetheeffectoftherapeutictargetingoflipidaccumulationinMDSCs on the generation of immune responses in melanoma models, and on tumor cell fate and response to targetedtherapy.